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Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells.

Prasanthi JR, Huls A, Thomasson S, Thompson A, Schommer E, Ghribi O - Mol Neurodegener (2009)

Bottom Line: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells.We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide.These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA. oghribi@medicine.nodak.edu.

ABSTRACT

Background: Activation of the liver x receptors (LXRs) by exogenous ligands stimulates the degradation of beta-amyloid 1-42 (Abeta42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxidized cholesterol products (oxysterols), 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), are endogenous activators of LXRs. However, the mechanisms by which these oxysterols may modulate Abeta42 levels are not well known.

Results: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells. We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide. Increased Abeta42 levels with 27-OHC are associated with increased levels of beta-amyloid precursor protein (APP) as well as beta-secretase (BACE1), the enzyme that cleaves APP to yield Abeta. Unchanged Abeta42 levels with 24-OHC are associated with increased levels of sAPPalpha, suggesting that 24-OHC favors the processing of APP to the non-amyloidogenic pathway. Interestingly, 24-OHC, but not 27-OHC, increases levels of the ATP-binding cassette transporters, ABCA1 and ABCG1, which regulate cholesterol transport within and between cells.

Conclusion: These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling Abeta42 levels in AD.

No MeSH data available.


Related in: MedlinePlus

24-OHC increases processing of APP via the non-amyloidogenic pathway. Western blot (a) and densitometric analyses (b) demonstrating increased levels of sAPPα in medium of 24-OHC-treated cells. Treatment with 27-OHC or a mixture of 24-OHC + 27-OHC did not influence sAPPα levels. Levels of Aβ40 were not affected by treatment with 24-OHC, 27-OHC, or a mixture of 24-OHC + 27-OHC compared to levels in control cells (c). *p < 0.05 (One way ANOVA followed by Dunnett's multiple comparison test).
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Figure 4: 24-OHC increases processing of APP via the non-amyloidogenic pathway. Western blot (a) and densitometric analyses (b) demonstrating increased levels of sAPPα in medium of 24-OHC-treated cells. Treatment with 27-OHC or a mixture of 24-OHC + 27-OHC did not influence sAPPα levels. Levels of Aβ40 were not affected by treatment with 24-OHC, 27-OHC, or a mixture of 24-OHC + 27-OHC compared to levels in control cells (c). *p < 0.05 (One way ANOVA followed by Dunnett's multiple comparison test).

Mentions: Extracellular sAPPα levels were determined with Western blot analysis in cell medium of control and of cells treated with 24-OHC, 27-OHC, and 24-OHC+27-OHC. Treatment with 24-OHC led to a substantial increase in sAPPα levels (Fig. 4a and 4b). No significant changes in sAPPα levels were observed in cells treated with 27-OHC or with a mixture of 24-OHC+27-OHC when compared to control cells (Fig. 4a and 4b). These results suggest that 24-OHC favors the processing of APP via the non-amyloidogenic pathway that precludes Aβ42 production.


Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells.

Prasanthi JR, Huls A, Thomasson S, Thompson A, Schommer E, Ghribi O - Mol Neurodegener (2009)

24-OHC increases processing of APP via the non-amyloidogenic pathway. Western blot (a) and densitometric analyses (b) demonstrating increased levels of sAPPα in medium of 24-OHC-treated cells. Treatment with 27-OHC or a mixture of 24-OHC + 27-OHC did not influence sAPPα levels. Levels of Aβ40 were not affected by treatment with 24-OHC, 27-OHC, or a mixture of 24-OHC + 27-OHC compared to levels in control cells (c). *p < 0.05 (One way ANOVA followed by Dunnett's multiple comparison test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654562&req=5

Figure 4: 24-OHC increases processing of APP via the non-amyloidogenic pathway. Western blot (a) and densitometric analyses (b) demonstrating increased levels of sAPPα in medium of 24-OHC-treated cells. Treatment with 27-OHC or a mixture of 24-OHC + 27-OHC did not influence sAPPα levels. Levels of Aβ40 were not affected by treatment with 24-OHC, 27-OHC, or a mixture of 24-OHC + 27-OHC compared to levels in control cells (c). *p < 0.05 (One way ANOVA followed by Dunnett's multiple comparison test).
Mentions: Extracellular sAPPα levels were determined with Western blot analysis in cell medium of control and of cells treated with 24-OHC, 27-OHC, and 24-OHC+27-OHC. Treatment with 24-OHC led to a substantial increase in sAPPα levels (Fig. 4a and 4b). No significant changes in sAPPα levels were observed in cells treated with 27-OHC or with a mixture of 24-OHC+27-OHC when compared to control cells (Fig. 4a and 4b). These results suggest that 24-OHC favors the processing of APP via the non-amyloidogenic pathway that precludes Aβ42 production.

Bottom Line: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells.We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide.These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA. oghribi@medicine.nodak.edu.

ABSTRACT

Background: Activation of the liver x receptors (LXRs) by exogenous ligands stimulates the degradation of beta-amyloid 1-42 (Abeta42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxidized cholesterol products (oxysterols), 24-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), are endogenous activators of LXRs. However, the mechanisms by which these oxysterols may modulate Abeta42 levels are not well known.

Results: We determined the effect of 24-OHC and/or 27-OHC on Abeta generation in SH-SY5Y cells. We found that while 27-OHC increases levels of Abeta42, 24-OHC did not affect levels of this peptide. Increased Abeta42 levels with 27-OHC are associated with increased levels of beta-amyloid precursor protein (APP) as well as beta-secretase (BACE1), the enzyme that cleaves APP to yield Abeta. Unchanged Abeta42 levels with 24-OHC are associated with increased levels of sAPPalpha, suggesting that 24-OHC favors the processing of APP to the non-amyloidogenic pathway. Interestingly, 24-OHC, but not 27-OHC, increases levels of the ATP-binding cassette transporters, ABCA1 and ABCG1, which regulate cholesterol transport within and between cells.

Conclusion: These results suggest that cholesterol metabolites are linked to Abeta42 production. 24-OHC may favor the non-amyloidogenic pathway and 27-OHC may enhance production of Abeta42 by upregulating APP and BACE1. Regulation of 24-OHC: 27-OHC ratio could be an important strategy in controlling Abeta42 levels in AD.

No MeSH data available.


Related in: MedlinePlus